Anti-inflammatory 1-substituted-4,5-diaryl-2-(substituted-thio) imidazoles and their corresponding sulfoxides and sulfones

Abstract

Anti-inflammatory 1-substituted-4,5-diaryl-2-(substituted-thio) imidazoles and their corresponding sulfoxides and sulfones useful for treating arthritis and related diseases.

We claim: 
     
       1. A compound of the formula ##STR14## where n=0, 1, or 2; 
     
     
       R 1  =C 1  -C 6  alkyl; allyl; vinyl; --CH 2  COCH 3  ; --CH 2  S(O) m  CH 3 , where m=0, 1, or 2; mono- and polyhalo- C 1  -C 4  alkyl; R 2  and R 3 , the same or different= ##STR15## Y 1  and Y 2 , the same or different=hydrogen, C 1  -C 4  alkoxy, C 1  -C 4  alkyl, Cl, F, CF 3 , NH 2 , --N(CH 3 ) 2 , NO 2 , CH 3  S--, CH 3  SO 2  --, or Y 1  and Y 2  taken together forming a dioxymethylene bridge; provided, when R 1  =C 1  -C 4  alkyl, C 3  -C 4  haloalkyl with halogen substituted at the 3 or 4 position, allyl, or acetonyl, both Y 1  and Y 2  cannot be H;     R 4  =C 1  -C 6  alkyl, allyl, CH 2  CH 2  N(R 5 ) 2 , ##STR16##  2-tetrahydropyranyl,  2-tetrahydrofuranyl, ##STR17## where R 5  =methyl or ethyl;   R 6  =H or methyl;   R 7  =C 1  -C 3  alkyl, benzyl, -CH 2  CH 2  OCH 3  ##STR18## R 8  =C 1  -C 4  alkyl or benzyl; R 9  =C 1  -C 4  alkyl or benzyl;   R 10  =C 1  -C 6  alkyl;   R 11  =H, methyl or ethyl;   R 12  =H, methyl or ethyl;   R 13  =C 1  -C 6  alkyl;   R 14  =C 1  -C 6  alkyl;   R 15  =C 1  -C 4  alkyl;   Ar= ##STR19## where Y 3  =H, F, Cl, Br, C 1  -C 4  alkyl, C 1  -C 4  alkoxy or nitro; provided when ##STR20## then n must be 0.     
     
     
       2. A compound of claim 1 where R 1  =--CF 2  CF 2  H. 
     
     
       3. A compound of claim 1 where R 1  =--CF 3 . 
     
     
       4. A compound of claim 1 where R 2  and R 3  independently, ##STR21## where Y 1  =H, Cl, or F. 
     
     
       5. A compound of claim 1 where R 4  =alkoxycarbonyl, alkoxymethyl, benzyloxymethyl or pivaloyloxymethyl. 
     
     
       6. A compound of claim 1 where n=1 or 2. 
     
     
       7. A compound of claim 1 where R 1  =--CF 2  CF 2  H;   R 2  and R 3 , independently, ##STR22##  where Y 1  =H, Cl, or F; and R 4  =alkoxycarbonyl, alkoxymethyl, benzyloxymethyl or pivaloyloxymethyl.   
     
     
       8. A compound of claim 1 where R 1  =CF 3  ;   R 2  and R 3 , independently, ##STR23## where Y 1  =H, Cl, or F; and   R 4  =alkoxycarbonyl, alkoxymethyl, benzyloxymethyl or pivaloyloxymethyl.   
     
     
       9. The compound of claim 1: 1-benzyloxymethyl-4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole. 
     
     
       10. The compound of claim 1: 4,5-diphenyl-1-ethoxycarbonyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole. 
     
     
       11. The compound of claim 1: 1-benzyloxymethyl-4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole. 
     
     
       12. The compound of claim 1: 4,5-diphenyl-1-(2-tetrahydropyranyl)-2-trifluoromethylthioimidazole. 
     
     
       13. The compound of claim 1: 1-ethoxycarbonyl-4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylthio)imidazole. 
     
     
       14. The compound of claim 1: 1-ethoxycarbonyl-4(or 5)-(4-fluorophenyl)-5(or 4)-phenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole. 
     
     
       15. The compound of claim 1: 4,5-bis(4-fluorophenyl)-1-(pivaloyloxymethyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole. 
     
     
       16. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 1. 
     
     
       17. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 2. 
     
     
       18. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 3. 
     
     
       19. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 4. 
     
     
       20. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 5. 
     
     
       21. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 6. 
     
     
       22. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 7. 
     
     
       23. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of a compound of claim 8. 
     
     
       24. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of claim 9. 
     
     
       25. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of claim 10. 
     
     
       26. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of claim 11. 
     
     
       27. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of claim 12. 
     
     
       28. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of claim 13. 
     
     
       29. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of claim 14. 
     
     
       30. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective anti-arthritic amount of the compound of claim 15. 
     
     
       31. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 1. 
     
     
       32. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 2. 
     
     
       33. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 3. 
     
     
       34. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 4. 
     
     
       35. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 5. 
     
     
       36. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 6. 
     
     
       37. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 7. 
     
     
       38. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of a compound of claim 8. 
     
     
       39. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of the compound of claim 9. 
     
     
       40. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of the compound of claim 10. 
     
     
       41. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of the compound of claim 11. 
     
     
       42. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of the compound of claim 12. 
     
     
       43. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of the compound of claim 13. 
     
     
       44. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of the compound of claim 14. 
     
     
       45. A method of treating arthritis in a mammal in need of such treatment which comprises administering to the mammal an effective antiarthritic amount of the compound of claim 15. 
     
     
       46. A compound of claim 1 wherein at least one of R 2  and R 3  = ##STR24## where Y 1  =C 1  -C 4  alkoxy. 
     
     
       47. A compound of claim 1 wherein R 4  =--CH 2  OCH 2  ##STR25## 2-tetrahydropyranyl, 2-tetrahydrofuranyl or --SO 2  Ar. 
     
     
       48. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective analgesic amount of a compound of claim 46. 
     
     
       49. A method of treating pain in a mammal in need of such treatment which comprises administering to the mammal an effective analgesic amount of a compound of claim 46. 
     
     
       50. A compound of claim 1 where n=0, 1, or 2;   R 1  =C 1  -C 4  alkyl; allyl; vinyl; --CH 2  COCH 3  ; --CH 2  S(O) m  CH 3 , where m=0, 1, or 2; mono- and polyhalo- C 1  -C 4  alkyl;   R 2  and R 3 , the same or different= ##STR26## Y 1  and Y 2 , the same or different=hydrogen, C 1  -C 4  alkoxy, C 1  -C 4  alkyl, Cl, F, CF 3 , NH 2 , -N(CH 3 ) 2 , NO 2 , CH 3  S-, CH 3  SO 2  -, or Y 1  and Y 2  taken together forming a dioxymethylene bridge;   R 4  =C 1  -C 3  alkyl, methoxymethyl, benzyloxymethyl, methoxycarbonyl, ethoxycarbonyl, and 2-tetrahydropyranyl; provided, when R 1  =C 1  -C 4  alkyl, C 3  -C 4  haloalkyl with halogen substituted at the 3 or 4 position, allyl, or acetonyl, both Y 1  and Y 2  cannot be H.